Treatment of Alzheimer Disease

BRADFORD T. WINSLOW, MD, Swedish Family Medicine Residency, Littleton, Colorado

MARY K. ONYSKO, PharmD, University of Wyoming School of Pharmacy, Laramie, Wyoming
CHRISTIAN M. STOB, DO, Denver Health Medical Center, Denver, Colorado
KATHLEEN A. HAZLEWOOD, PharmD, University of Wyoming School of Pharmacy, Laramie, Wyoming

Alzheimer disease is the most common form of dementia, affecting more than one-third of Americans older than
85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neu-
rofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer dis-
ease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3
fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcho-
linesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild
improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these
effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diar-
rhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D -aspartate receptor antago-
nist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with
moderate to severe Alzheimer disease. Memantine can also be used
in combination with acetylcholinesterase inhibitors. Memantine is
generally well tolerated, but whether its benefits produce clinically
meaningful improvement is controversial. Although N-methyl-D -
aspartate receptor antagonists and acetylcholinesterase inhibitors
can slow the progression of Alzheimer disease, no pharmacologic
agents can reverse the progression. Atypical antipsychotics can
improve some behavioral symptoms, but have been associated with
increased mortality rates in older patients with dementia. There is

ILLUSTRATION BY JENNIFER FAIRMAN

conflicting evidence about the benefit of selegiline, testosterone,
and ginkgo for the treatment of Alzheimer disease. There is no evi-
dence supporting the beneficial effects of vitamin E, estrogen, or
nonsteroidal anti-inflammatory drug therapy. (Am Fam Physician.
2011;83(12):1403-1412. Copyright 2011 American Academy of
Family Physicians.)

A
Patient information: lzheimer disease affects approxi- characterized by total dependence on care-

A handout on Alzheimer mately 5.4 million Americans and
disease, written by the accounts for most cases of demen-
authors of this article, is
provided on page 1415. tia.1 Like other types of dementia,
it is characterized by progressive memory
loss and cognitive decline. Alzheimer disease
is usually diagnosed in persons older than
65 years, and its prevalence increases every
decade thereafter. Nearly one-half of Ameri-
cans 85 years and older have Alzheimer dis-
ease.1 Women are more commonly affected
than men. Patients with mild disease have
some functional dependence, such as trouble
managing finances.2 Patients with moder-
ate disease are more dependent on others,
often are unable to drive, and have difficulty
with bathing and shopping.2 Severe disease is
Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2011 American Academy of Family Physicians. For the private, noncom-
Junemercial use of one
15, 2011 individual
Volume user of the12Web site. All other rights reserved.
83, Number www.aafp.org/afp
Contact copyrights@aafp.org for copyrightAmerican
takers, and by motor and balance impair-
ments.2 There is no consensus on the best
method to assess the severity of Alzheimer
disease to guide treatment. Many physi-
cians are familiar with the Mini-Mental State
Examination. Another potentially useful
tool to assess disease severity is the Clini-
cal Dementia Rating (Table 1).3,4 This article
reviews recent evidence and guidelines on the
management of Alzheimer disease.
Pathophysiology
The pathophysiology of Alzheimer disease
is complex and multifactorial. Character-
istic pathologic features include the accu-
mulation of amyloid cerebral plaques and

questions and/or
Familypermission 1403
requests.
Physician
Alzheimer Disease
SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References

Acetylcholinesterase inhibitors are modestly A 12 Medications

effective in patients with mild to moderate
Alzheimer disease, although limited by their
Acetylcholinesterase inhibitors reversibly
adverse effects. bind and inactivate the enzyme that degrades
Combination therapy with an acetylcholinesterase B 27 acetylcholine, which is involved in memory.12
inhibitor and memantine (Namenda) should be Donepezil (Aricept) is the only acetylcholin-
considered in patients with moderate to severe
esterase inhibitor approved for use in all stages
Alzheimer disease.
Atypical antipsychotic agents can improve some B 31, 33
of the disease. The N-methyl-D -aspartate
behavioral manifestations of Alzheimer disease receptor antagonist memantine (Namenda)
but are associated with increased mortality in is approved for treating moderate to severe
older patients. disease, and is thought to prevent excitatory
Nonsteroidal anti-inflammatory drugs, vitamin E, B 34-43, amino acid neurotoxicity without interfering
testosterone, estrogen, statins, and insulin 46-49
sensitizers are not recommended for the with the physiologic actions of glutamate, a
treatment of Alzheimer disease. neurotransmitter necessary for learning and
Physicians should consider discontinuing C 16 memory.13 Studies of these drugs have usu-
treatment for Alzheimer disease in patients who ally assessed effectiveness using one of sev-
continue to decline despite maximal therapy.
eral scales, such as the Alzheimers Disease
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited- Assessment Scale for Cognition (ADAS-cog;
quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual a 70-point scale), the Alzheimers Disease
practice, expert opinion, or case series. For information about the SORT evidence Cooperative Study Activities of Daily Living
rating system, go to http://www.aafp.org/afpsort.xml.
inventory (ADCS-ADL; a 54-point scale),
or the Severe Impairment Battery (SIB; a
neurofibrillary tangles of abnormally insoluble tau, an 100-point scale). In general, to be clinically significant
axonal protein. Synaptic levels of acetylcholine decrease (defined as a noticeable improvement by the patient or
as a result of cholinergic neuron involvement. Many caregiver), an increase should be at least 10 percent of the
other factors may contribute to the pathophysiology, scale length (i.e., 7 points on the ADAS-cog, 5 points on
such as depletion of other neurotransmitters, loss of the ADCS-ADL, or 10 points on the SIB).
neural synapses, mitochondrial dysfunction, oxidative
stress, inflammation, ischemia, insulin signaling, and ACETYLCHOLINESTERASE INHIBITORS
cholesterol metabolism.5 Emerging treatments may be Acetylcholinesterase inhibitors are first-line agents
directed at these pathways. for the treatment of mild to moderate Alzheimer dis-
ease, according to existing guidelines.2,12,14-20 Most ran-
Prevention domized controlled trials and systematic reviews have
Numerous studies have assessed factors that may affect found no notable differences in effectiveness among
the incidence of Alzheimer disease, such as the use of the various acetylcholinesterase inhibitors.21 Despite
dietary supplements and pharmacologic agents, diet, small variations in mechanisms of action, these agents
socioeconomic factors, medical conditions, and environ- have varying adverse effect profiles (Table 221-23). The
mental exposures. Although many studies have found an most common adverse effects are nausea, vomiting,
association, they have not proven that the relationship and diarrhea; cardiovascular and neurologic adverse
is causal or that modification of these factors reduces effects are comparable. The incidence of adverse effects
the risk of Alzheimer disease. Of the prevention strat- is directly related to the dose administered.23 Rivastig-
egies studied, treatment of hypertension, consumption mine (Exelon) patches may be better tolerated than oral
of omega-3 fatty acids, physical activity, and cognitive rivastigmine.24 Tacrine is no longer available because of
engagement demonstrate some promise. However, larger safety and tolerability concerns.
randomized controlled trials are needed to further assess A Cochrane review concluded that in patients with
these results.6-10 A recent consensus statement from Alzheimer disease, treatment with donepezil, galan-
the National Institutes of Healths State-of-the-Science tamine (Razadyne), or rivastigmine for six months to
Conference on Preventing Alzheimers Disease and Cog- one year resulted in slightly improved cognitive func-
nitive Decline concluded that the current evidence is tion by an average of 2.7 points on the ADAS-cog.12
insufficient to support the association of any modifiable Improvements in behavior and activities of daily liv-
factor, pharmacologic agent, or dietary supplement with ing also have been noted in patients treated with one of
a reduction in the risk of Alzheimer disease.11 these three agents; however, none of the medications has

1404 American Family Physician www.aafp.org/afp Volume 83, Number 12 June 15, 2011
 Alzheimer Disease
Table 1. Clinical Dementia Rating

Impairment

None (0) Questionable (0.5) Mild (1) Moderate (2) Severe (3)

Memory No memory loss or Consistent slight Moderate memory loss; Severe memory loss; Severe memory
slight inconsistent forgetfulness; more marked for recent only highly learned loss; only
forgetfulness partial events; defect interferes material retained; fragments remain
recollection of with everyday activities new material
events; benign rapidly lost
forgetfulness

Orientation Fully oriented Fully oriented Moderate difficulty with Severe difficulty with Oriented to person
except for time relationships; time relationships; only
slight difficulty oriented for place at usually disoriented
with time examination; may to time, often to
relationships have geographic place
disorientation elsewhere

Judgment Solves everyday Slight impairment Moderate difficulty in Severely impaired in Unable to make
and problems and in solving solving problems, solving problems, judgments or
problem handles business problems, determining similarities determining solve problems
solving and financial affairs determining and differences; social similarities and
well; judgment similarities and judgment usually differences; social
good in relation to differences maintained judgment usually
past performance impaired

Community Independent function Slight impairment Unable to function No pretense of No pretense of

affairs at usual level in in these activities independently at these independent independent
job, shopping, and activities, although function outside of function outside
volunteer and social may still be engaged in home; appears well of home;
groups some; appears normal enough to be taken appears too ill
to casual inspection to functions outside to be taken to
a family home functions outside
a family home

Home and Life at home, Life at home, Mild but definite Only simple chores No significant
hobbies hobbies, and hobbies, and impairment of function preserved; interests function in home
intellectual interests intellectual at home; more difficult very restricted and
well maintained interests slightly chores abandoned; more poorly maintained
impaired complicated hobbies and
interests abandoned

Personal Fully capable of self- Fully capable of Needs prompting Requires assistance Requires much help
care care self-care in dressing, with personal
hygiene, keeping care; frequent
of personal effects incontinence

Global Clinical Dementia Rating score: 0 = normal cognitive function; 0.5 = very mild dementia; 1 = mild dementia; 2 = moderate dementia;
3 = severe dementia.
NOTE: Only one box should be marked in each category. Score only as decline from previous usual level due to cognitive loss, not impairment due
to other factors. If the physician feels that the patient could be rated in either of the two adjacent boxes, the box of greater impairment should be
checked. The global Clinical Dementia Rating score is derived from the scores in each of the six categories. Memory is the primary category, with all
others being secondary. The overall score is equivalent to the memory portion score if at least three secondary categories are given the same score
as the memory portion, or if one-half of the secondary categories are greater and one-half are less than the memory portion score. If at least three
secondary categories score greater or less than the memory portion, the overall score is equal to the score of the majority of the secondary categories.
Physicians using this tool should participate in the Brief Training and Reliability Protocol, which can be completed online through Washington Univer-
sitys Alzheimers Disease Research Center at http://alzheimer.wustl.edu/.
Adapted with permission from Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2413, with
additional information from reference 4.

a large treatment effect, and the clinical significance of
these effects is questionable. Another systematic review
concluded that, despite statistical significance, the
improvement in patients with dementia taking acetyl-
cholinesterase inhibitors was clinically marginal (0.1 to
5.3 points on the ADAS-cog).21 Additional trials are
needed to determine the benefits of long-term therapy
and whether these agents are effective in patients with
moderate to severe Alzheimer disease. It is reasonable to
discontinue treatment if there is no improvement within

June 15, 2011 Volume 83, Number 12 www.aafp.org/afp American Family Physician1405
Alzheimer Disease
Table 2. Medications for Treating Alzheimer Disease

Medication* Common dosage Pharmacologic actions22 Adverse effects and expected incidence (overall %)22,23

Acetylcholinesterase inhibitors
Donepezil 10 mg per day Centrally active, reversible, Any adverse effect (15.1 to 71.3)
(Aricept) and noncompetitive Discontinuation because of adverse effects (2.5 to 14.6)
acetylcholinesterase inhibitor
Any gastrointestinal adverse effect (4.5 to 23.8)
Nausea (1.4 to 19)
Diarrhea (0 to 15)
Headache (2.4 to 14)
Insomnia (0 to 14)
Agitation (3 to 12.5)
Dizziness (10)
Vomiting (0 to 9)

Galantamine 8 mg twice per day, Reversible, competitive Any adverse effect (31.9 to 55)
(Razadyne) or 16 mg extended- acetylcholinesterase inhibitor Discontinuation because of adverse effects (2.4 to 21.1)
release formulation that also acts on nicotinic
Any gastrointestinal adverse effect (24)
once per day acetylcholine receptors
Nausea (0 to 24)
Vomiting (1.9 to 13)
Cardiac arrhythmia (3.9 to 12.5)
Diarrhea (5.8 to 12)
Confusion (11.1)
Headache (8 to 11)
Dizziness (1 to 10)

Rivastigmine 6 mg orally twice per Reversible carbamate Any adverse effect (20.1 to 78)
(Exelon) day or 9.5 mg per acetylcholinesterase inhibitor Discontinuation because of adverse effects (3.1 to 40)
24-hour patch that interacts preferentially with
Nausea (0.8 to 47)
acetylcholinesterase G1
Any gastrointestinal adverse effect (6.3 to 39)
Vomiting (0.8 to 31)
Weight loss (3 to 26)
Dizziness (2 to 21)
Diarrhea (0 to 19)
Cardiac arrhythmia (0 to 18.8)
Loss of appetite (3 to 17)

NMDA receptor antagonist

Memantine 10 mg twice per day Low to moderate affinity NMDA Adverse effects and dropout rates not statistically
(Namenda) receptor antagonist that binds to different from placebo
NMDA receptoroperated cation Dizziness (5 to 7)
channels; prevents glutamatergic
Confusion (6)
overstimulation at NMDA receptor
Headache (6)
Diarrhea (2 to 5)
Vomiting (2 to 3)

NA = not available; NMDA = N-methyl- D -aspartate.

*Medications do not reverse the symptoms of dementia but may slow their course.
Adverse effects are listed in order of expected incidence, from most to least likely.
Systematic reviews have found no significant differences in effectiveness among acetylcholinesterase inhibitors.
Estimated retail price of one months treatment based on information obtained at http://www.drugstore.com (accessed March 9, 2011).
Information from references 21 through 23.

six to eight weeks. Therapy may be restarted if symp- MEMANTINE

toms worsen after the medication is tapered, because Memantine prevents excessive glutamatergic activity. A
acetylcholinesterase inhibitors may be more effective for Cochrane review concluded that memantine at a dos-
symptomatic control than previously recognized.25 age of 20 mg per day over six months slightly improved

1406 American Family Physician www.aafp.org/afp Volume 83, Number 12 June 15, 2011

Evidence of benefit21
A dosage of 5 to 10 mg per day
mildly improves cognition and
global function
No benefit seen in patients with
mild cognitive impairment
May slow development of disease
in the short term, but not after
36 months
Improves cognition and global function
Inconsistent evidence for change
in activities of daily living
Short duration of studies limits
interpretation of use beyond
six months
Effect size on cognition not statistically
significant
May have some benefit in activities of
daily living up to 12 months
A dosage of 20 mg per day has positive
effect on cognition in patients with
mild, moderate, or severe Alzheimer
disease
Mood, behavior, and activities of daily
living improved in patients with
moderate to severe Alzheimer disease
cognition (3 points on the SIB) and ability to do activi-
ties of daily living (1.3 points on the ADCS-ADL) in
patients with moderate to severe Alzheimer disease.
The effect on cognition was statistically significant in
June 15, 2011 Volume 83, Number 12
Cost of generic (brand)
$180 ($276)
$140 ($225) for 8 mg
twice per day
$120 ($226) for 16 mg
extended release once
per day
Capsules: NA ($257)
Patches: NA ($255)
NA ($210)
www.aafp.org/afp
Alzheimer Disease
patients with mild to moderate dementia (1 point on the
ADAS-cog) but is unlikely to have clinical significance.
A small reduction in agitation was seen in patients tak-
ing memantine. Seventeen patients with moderate to
severe Alzheimer disease would need to be treated for six
months to prevent one episode of agitation.13
A meta-analysis concluded that memantine was inef-
fective for patients with mild Alzheimer disease, and the
benefits for patients with moderate Alzheimer disease
were inconsistent.26
Memantine is generally well tolerated and is often
used with acetylcholinesterase inhibitors. One study
randomized patients taking donepezil for moderate to
severe Alzheimer disease to receive 20 mg of meman-
tine or placebo every day for 24 weeks.27 Patients tak-
ing memantine showed mild improvement in cognition
(+0.9 points versus 2.5 points with placebo on the
SIB) and activities of daily living (2.0 points versus
3.4 points with placebo on the ADCS-ADL). Another
study evaluated the effectiveness and safety of 20 mg of
memantine per day for 24 weeks in patients already tak-
ing donepezil, rivastigmine, or galantamine for mild to
moderate Alzheimer disease.28 Adding memantine was
not associated with a statistically significant improve-
ment compared with placebo. The lack of adverse effects
was consistent with findings in other memantine mono-
therapy studies.13,28
Guidelines from the National Institute for Health and
Clinical Excellence cite a study that found no improve-
ment with memantine compared with placebo in
patients who had moderate to severe Alzheimer disease.14
Patients taking memantine may have problems with
adherence because it is typically taken twice per day. A
once-daily extended-release formulation of memantine
was approved by the U.S. Food and Drug Administration
in June 2010.22
SELEGILINE
Selegiline (Eldepryl) is a monoamine oxidase type B
inhibitor with minimal anticholinergic effects. A
Cochrane review analyzed 17 double-blind, random-
ized, placebo-controlled trials evaluating selegiline at a
dosage of 10 mg per day for the treatment of Alzheimer
disease. The authors concluded that cognition improved
at four to six weeks in some trials; however, there were no
differences after six weeks.29 The benefits were found pri-
marily in two studies; other trials did not support these
findings. No differences in adverse effects were noted
compared with placebo. Currently, there is not enough
evidence to recommend selegiline for the treatment of
Alzheimer disease.
American Family Physician1407
Alzheimer Disease
ANTIPSYCHOTICS
Antipsychotics are not approved by the U.S. Food and
Drug Administration for the treatment of Alzheimer dis-
ease, although they are commonly used to treat behavioral
symptoms. Evidence suggests that olanzapine (Zyprexa)
and risperidone (Risperdal) reduce aggression, and ris-
peridone reduces psychosis in patients with Alzheimer
disease.30 The Clinical Antipsychotic Trials of Interven-
tion Effectiveness protocol for Alzheimer disease assessed
the effects of atypical antipsychotics on psychiatric and
behavioral symptoms.31 It included 421 outpatients with
Alzheimer disease and psychosis or agitated/aggressive
behavior. Patients were randomized to receive olanzap-
ine, quetiapine (Seroquel), risperidone, or placebo for up
to 36 weeks. There were no clinically or statistically sig-
nificant differences in functioning, care needs, or quality
of life between patients taking antipsychotics and those
taking placebo. Some clinical symptoms improved, such
as anger, aggression, and paranoia. Patients taking olan-
zapine experienced worsening functional ability at week
12 compared with those taking placebo. A small random-
ized, double-blind, placebo-controlled trial failed to dem-
onstrate effectiveness of quetiapine or rivastigmine for
treatment of agitation in patients with Alzheimer disease
in care facilities after 26 weeks.32 At six weeks, a statisti-
cally significant decline in cognition was noted in patients
taking quetiapine compared with those taking placebo.
Older patients with dementia who are treated with
atypical antipsychotics have a twofold higher mortality
rate than those taking placebo.33 One study found that
new use of atypical antipsychotics was associated with
an increased risk of death at 30 days both in community-
dwelling patients (hazard ratio = 1.31; 95% confidence
interval, 1.02 to 1.70) and in those living in long-term
care facilities (hazard ratio = 1.55; 95% confidence inter-
val, 1.15 to 2.07).33 Most of those deaths were related to
cardiovascular or infectious causes, possibly because
antipsychotics can prolong QT interval and cause seda-
tion, which may increase the risk of aspiration. Other
common adverse effects of antipsychotics include gait
disturbances and extrapyramidal effects. Using atypi-
cal antipsychotics to treat behavioral symptoms such as
agitation in patients with Alzheimer disease generally
should be avoided because of adverse effects, although
these agents may be appropriate in some situations.
Ineffective Therapies
Estrogen has been studied for the prevention and treat-
ment of dementia. A Cochrane review found no beneficial
effect of long-term estrogen use on cognitive function in
patients with Alzheimer disease.34 Estrogen does not
1408 American Family Physician www.aafp.org/afp Volume 83, Number 12
enhance the effects of acetylcholinesterase inhibitors; no
benefit was found when it was used in combination with
rivastigmine.35
An updated Cochrane review concluded that there is
no evidence supporting the use of vitamin E for the pre-
vention or treatment of Alzheimer disease, and it may
be harmful in higher doses.36 Studies have demonstrated
no beneficial effect of nonsteroidal anti-inflammatory
drugs for the treatment of Alzheimer disease.37-41 Statins
and insulin sensitizers have not demonstrated benefit in
clinical trials in patients with Alzheimer disease.42,43 Sys-
tematic reviews have found no clear benefit of lecithin or
acetyl-L-carnitine.44,45
Therapies with Conflicting Evidence
TESTOSTERONE
There is conflicting evidence on the benefit of testoster-
one in men with Alzheimer disease. Two randomized,
double-blind, placebo-controlled studies demonstrated
benefit in visuospatial cognition, but it is unclear if
this effect is clinically meaningful.46,47 A randomized,
placebo-controlled trial examined the effect of 1% tes-
tosterone gel supplementation (75 mg per day) in men
with mild to moderate Alzheimer disease over a period
of six months.48 No statistically significant benefits
were detected, although testosterone treatment mildly
improved patients quality of life. A randomized, double-
blind, placebo-controlled trial of men older than
65 years with limited mobility and low testosterone lev-
els evaluated treatment with testosterone gel or placebo.
The results showed a significantly increased incidence
of adverse cardiovascular effects in the treatment group
over six months (22 versus 5 percent in the placebo
group; P = .05; number needed to harm = 6).49 Because
of the risk of serious adverse effects and the paucity of
clinically helpful effects, testosterone therapy in men
with Alzheimer disease is not recommended.
GINKGO
A Cochrane Review evaluated 36 studies of ginkgo for
the treatment of cognitive impairment and dementia.50
All but one study used the standard ginkgo extract EGb
761, at a dosage of 80 to 600 mg per day. Ginkgo was not
associated with a consistent, clinically significant benefit
in persons with Alzheimer disease. A European study
of 96 patients with Alzheimer disease demonstrated
equal effectiveness among a prescription ginkgo extract
(240 mg per day), donepezil (5 to 10 mg per day), and
a combination of the two agents.51 Because ginkgo is
not available as a regulated prescription product in the
United States, it is possible that the variability in dietary
June 15, 2011
 Alzheimer Disease
Table 3. Summary of Guidelines for the Treatment of Alzheimer Disease

Year of Recommendations on
Organization recommendation Recommended therapy Suggested monitoring discontinuing therapy

American Academy of 2008 Acetylcholinesterase inhibitors for No recommendations Discontinue with loss
Family Physicians and mild to moderate disease of effectiveness
American College of Memantine (Namenda) for
Physicians15 moderate to severe disease

American Geriatrics 2009 Acetylcholinesterase inhibitors for MMSE, Clinical Dementia Discontinue if the
Society16 mild to moderate disease Rating, and Functional patient develops
Memantine plus donepezil (Aricept) Assessment Staging severe impairment
for moderate to severe disease scale
Caregivers should commit to a trial
treatment period of at least three
months

American Psychiatric 2007 Acetylcholinesterase inhibitors for Every three to six months Discontinue with
Association2 mild to moderate disease if patient is clinically patient preference
Memantine plus donepezil for stable; more frequently or loss of
moderate to severe disease if adjusting medications effectiveness

California Workgroup 2008 Acetylcholinesterase inhibitors for After two to four weeks Discontinue before
on Guidelines for mild to moderate disease for adverse effects, surgery or if there
Alzheimers Disease Memantine plus an then every six months is continued
Management17 acetylcholinesterase inhibitor for to monitor effect on deterioration at
moderate to severe disease cognition and function pretreatment rate
after six months

Canadian Consensus 2007 Acetylcholinesterase inhibitors for Regularly Discontinue with

Conference on mild to moderate disease patient preference,
the Diagnosis Memantine plus an physician judgment,
and Treatment of acetylcholinesterase inhibitor for or severe disease
Dementia18 moderate to severe disease

European Federation 2007 Acetylcholinesterase inhibitors for
of Neurological mild to moderate disease
Societies19 Memantine plus an
acetylcholinesterase inhibitor for
moderate to severe disease
Regular follow-up Discontinue if rapid
to assess cognitive worsening or an
function, activities apparent loss of
of daily living, and effectiveness
behavioral symptoms

Italian Association of 2005 Acetylcholinesterase inhibitors for
Psychogeriatrics20 mild to severe disease
Memantine for moderate to severe
disease
Cognitive function, Discontinue if loss of
activities of daily effectiveness
living, and behavioral
and psychological
symptoms

National Institute for 2006 Acetylcholinesterase inhibitors for MMSE and global, Discontinue with
Health and Clinical moderate disease functional, and patient or caregiver
Excellence14 behavioral assessment preference, or
every six months physician judgment

MMSE = Mini-Mental State Examination.

Information from references 2, and 14 through 20.

supplement quality may account for the difference in
findings. Clinical evidence appears to support the safety
of ginkgo, with no additional adverse effects reported
compared with placebo. However, possible drug-
supplement interactions must be considered in patients
with Alzheimer disease who use ginkgo, especially the
risk of bleeding with the use of aspirin, nonsteroidal
anti-inflammatory drugs, or anticoagulants. This is
noteworthy because many patients with Alzheimer dis-
ease take aspirin for cardiovascular health.
Approach to the Patient
Guidelines on the treatment of Alzheimer disease are
available from a number of organizations (Table 32,14-20),
including one developed by the American Acad-
emy of Family Physicians, in conjunction with the

June 15, 2011 Volume 83, Number 12 www.aafp.org/afp American Family Physician1409
Alzheimer Disease

American College of Physicians.15 All guide-

Treatment of Alzheimer Disease lines emphasize the importance of educating
Patient is diagnosed with Alzheimer disease patients and their families about the disease
Educate the patient and family about disease process process and its expected course. Early refer-
Discuss medicolegal issues ral to local support groups is recommended,
Provide information on support groups and medicolegal issues such as driving and
Refer to subspecialist if unable to perform appropriate end-of-life planning should be addressed.
follow-up, or if the patient or family requests a referral
Recommendations regarding pharmacologic
treatment are described in Table 2,21-23 and
Assess baseline functionality, medical and psychiatric state a suggested algorithm for the treatment of
Minimize use of any anticholinergic medication Alzheimer disease is presented in Figure 1.
Review medication options, including potential The decision to treat with medication should
effectiveness, adverse effects, and cost
be shared with the patient and caregivers,
including a discussion of the modest clini-
cal benefit, adverse effects, and cost. Physi-
Patients condition is Patients condition is considered
cians should consider discontinuing therapy
considered mild at diagnosis moderate to severe at diagnosis in patients who continue to decline despite
maximal therapy.16 The National Institute on
Aging and the Alzheimers Association have
Begin treatment with Begin treatment with
acetylcholinesterase inhibitor acetylcholinesterase inhibitor, with
released recommendations on the diagnosis
or without memantine (Namenda) of dementia and mild cognitive impairment
from Alzheimer disease; however, these
Reevaluate patient two to four guidelines do not address the treatment of
weeks after medication initiation; Go to A
treat serious adverse effects Alzheimer disease and do not recommend
the clinical use of biomarkers.52,53

Possible Future Treatments

Patient tolerates medication Patient is not tolerating medication, or Many potential therapeutic agents are cur-
and is using stable dose his or her condition deteriorates based
rently under investigation for the treatment
on functionality and caregivers input
of Alzheimer disease. Amyloid precursor
Follow up every three to six protein and enzymes involved in -amyloid
months, and continue treatment Change to another formation are thought to contribute to
while patients condition is stable acetylcholinesterase inhibitor
genetic forms of Alzheimer disease; there-
fore, interventions to reduce amyloid plaque
Reevaluate patient two to four weeks after burden by altering amyloid metabolism
medication adjustment; treat serious adverse effects are being evaluated. Immunotherapy to
promote clearance of -amyloid from the
central nervous system is being assessed.
Advanced glycation end products are asso-
Patients condition deteriorates to ciated with aging. The advanced glycation
moderate to severe Alzheimer disease
end products receptor is a potential target
Add memantine
to decrease plaque formation and inflam-
mation. Other potential treatments include
resveratrol, a compound from the skin of red
A Discontinue medications if:
grapes that may have beneficial effects on
Patient does not adhere to treatment
aging in mice, and latrepirdine, a N-methyl-
Deterioration continues
D -aspartate receptor antagonist that may also
Patient develops serious comorbid disease or is terminally ill
Patient or caregiver chooses to discontinue treatment weakly inhibit acetylcholinesterase, which
may improve cognitive performance and is
currently in phase 3 trials. Agents targeted
Figure 1. Algorithm for the treatment of Alzheimer disease. against tau are other possible options.54

1410 American Family Physician www.aafp.org/afp Volume 83, Number 12 June 15, 2011

The Authors
BRADFORD T. WINSLOW, MD, FAAFP, is program director at the Swedish
Family Medicine Residency, Littleton, Colo.
MARY K. ONYSKO, PharmD, BCPS, is assistant professor of pharmacy
practice at the University of Wyoming School of Pharmacy, Laramie.
CHRISTIAN M. STOB, DO, is a staff physician at the Denver (Colo.) Health
Medical Center.
KATHLEEN A. HAZLEWOOD, PharmD, BCPS, is assistant professor of phar-
macy practice at the University of Wyoming School of Pharmacy.
Address correspondence to Bradford T. Winslow, MD, FAAFP, Swedish
Family Medicine Residency, 191 E. Orchard Rd., Ste. 200, Littleton, CO
80121. Reprints are not available from the authors.
Author disclosure: No relevant financial affiliations to disclose.
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